Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seoul 03760, Korea.
Department of Pharmacy, Ewha Womans University, 52, Ewhayeodae-gil, Seoul 03760, Korea.
Biochem J. 2021 Jan 15;478(1):235-245. doi: 10.1042/BCJ20200677.
Flavonoids play beneficial roles in various human diseases. In this study, a flavonoid library was employed to probe inhibitors of d-glycero-β-d-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei (BpHldC) and two flavonoids, epigallocatechin gallate (EGCG) and myricetin, have been discovered. BpHldC is one of the essential enzymes in the ADP-l-glycero-β-d-manno-heptose biosynthesis pathway constructing lipopolysaccharide of B. pseudomallei. Enzyme kinetics study showed that two flavonoids work through different mechanisms to block the catalytic activity of BpHldC. Among them, a docking study of EGCG was performed and the binding mode could explain its competitive inhibitory mode for both ATP and βG1P. Analyses with EGCG homologs could reveal the important functional moieties, too. This study is the first example of uncovering the inhibitory activity of flavonoids against the ADP-l-glycero-β-d-manno-heptose biosynthesis pathway and especially targeting HldC. Since there are no therapeutic agents and vaccines available against melioidosis, EGCG and myricetin can be used as templates to develop antibiotics over B. pseudomallei.
类黄酮在各种人类疾病中发挥有益作用。在这项研究中，使用了一个类黄酮文库来探测伯克霍尔德氏菌（B. pseudomallei）d-甘油-β-d-甘露庚糖-1-磷酸腺苷酰转移酶（BpHldC）的抑制剂，发现了两种类黄酮，表没食子儿茶素没食子酸酯（EGCG）和杨梅素。BpHldC 是构建伯克霍尔德氏菌脂多糖的 ADP-l-甘油-β-d-甘露庚糖生物合成途径中的必需酶之一。酶动力学研究表明，两种类黄酮通过不同的机制阻断 BpHldC 的催化活性。其中，对 EGCG 进行了对接研究，结合模式可以解释其对 ATP 和βG1P 的竞争性抑制模式。对 EGCG 同源物的分析也可以揭示重要的功能部分。这项研究是首次揭示类黄酮对 ADP-l-甘油-β-d-甘露庚糖生物合成途径的抑制活性，特别是针对 HldC。由于目前尚无针对类鼻疽的治疗药物和疫苗，因此 EGCG 和杨梅素可用作针对伯克霍尔德氏菌的抗生素开发模板。
